chr8-99275103-G-T

Variant names:

• chr8-99275103-G-T
• rs770484465
• NM_017890.5:c.2673G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152564.5(VPS13B):​c.2673G>T​(p.Leu891Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000757 in 1,453,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.79
• Publications: 1 publications found

Genes affected

VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

VPS13B Gene-Disease associations (from GenCC):

• Cohen syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152564.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.2673G>T	p.Leu891Phe	missense	Exon 19 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.2673G>T	p.Leu891Phe	missense	Exon 19 of 62	NP_689777.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.2673G>T	p.Leu891Phe	missense	Exon 19 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.2673G>T	p.Leu891Phe	missense	Exon 19 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000355155.6	TSL:1	n.2673G>T		non_coding_transcript_exon	Exon 19 of 28	ENSP00000347281.2	A0A8C8KE22

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000363 AC: 9 AN: 247790 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000497

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000757 AC: 11 AN: 1453848 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722880

African (AFR) AF: 0.00 AC: 0 AN: 33226

American (AMR) AF: 0.00 AC: 0 AN: 43976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25932

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39456

South Asian (SAS) AF: 0.00 AC: 0 AN: 83776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108646

Other (OTH) AF: 0.0000666 AC: 4 AN: 60030

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Cohen syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.30
Sift	Benign	0.43	T
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.21		Gain of methylation at K890 (P = 0.0311)
MVP		0.71
MPC		0.20
ClinPred		0.23	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.62
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770484465; hg19: chr8-100287331;